DESCRIPTION: Vasoactive intestinal peptide (VIP) is a potent regulator of neuroblast proliferation and survival in vitro. Administration of VIP antagonist to pregnant mice produced a pronounced microcephaly condition in offspring, providing a new model for human brain disease. VIP effects in tissue culture can also be brought about by the structurally-related neuropeptide pituitary adenylate cyclase activating peptide (PACAP). Despite the demonstrated capacity of these peptides to regulate CNS development, investigators have been unable to show that VIP or PACAP is expressed in embryonic CNS of mice at early stages. Thus, the current model contends that VIP is derived transplacentally from the mother, and thereby acts as a global regulator of embryonic CNS development. To challenge this model , sensitive in situ hybridization protocols to detect mRNA for these ligands and their receptors was developed. This combined with data obtained by Northern analyses suggest that the VIP/PACAP ligand/receptor system may be operational within the embryo at the earliest stages of neurogenesis. It is thus proposed that VIP and PACAP are derived from the embryo and act in local domains to regulate CNS development. Two novel potential target populations for VIP and PACAP were identified by this analysis, neuroepithelial cells and microglia. It is proposed that VIP and PACAP regulate the proliferation of these cells. This will be tested using dispersed cell and short-term cultures of intact embryos. In addition, the unexplained ability of these peptides to induce proliferation in some cell populations and cell cycle withdrawal in others will be examined. It is hypothesized that the differences are due to G-protein coupling of receptors to different signal transduction pathways. This will be tested using a combination of pharmacological, molecular, and biochemical approaches, including analysis of the Rs/Raf/MAP kinase pathway. The results are expected to provide important mechanistic information on how these neuropeptides play important roles in CNS development, as well as in nerve injury, neurological tumors, and degenerative diseases of the nervous system.